Process for the conversion of 3-enol ethers of 3-keto-delta**4-steroids unsubstituted at c4 and c6 to the corresponding 3-keto-delta**4-6-methylene compounds

ABSTRACT

THIS INVENTION RELATES TO NOVEL AND GENERAL PROCESSES FOR THE CONVERSION FO THE 3-ENOL ETHERS (I) OF 3-KETO -$4STEROIDS, UNSUBSTITUTED AT THE 4 AND 6 POSITIONS, OF THE ANDROSTANE, 19-NORANDROSTANE, PREGNANE, 19-NORPREGNANE, STIGMASTANE AND SPIROSTNE SERIES INTO THE CORRESPONDING 3-KETO-$4-6B-(N,N-DISUBSTITUTED) AMINOMETHYL DERIVATIVES (II), AND THENCE TO THEIR 6-METHYLENE COUNTERPARTS (III). THE COMPOUNDS OF FORMULA III HAVE ANABOLIC, ANDROGENIC ANTI-FERTILITY, ANTI-INFLAMMATORY AND ESTROGENIC ACTIVITIES, AND ARE CONSEQUENTLY USEFUL IN TREATING MAMMALS, INCLUDING HUMANS, BIRDS AND OTHER ANIMALS IN THOSE CONDITIONS AND/OR AILMENTS WHERE SUCH ACTIVITIES ARE DESIRED. FOR EXAMPLE, IN PREVENTING PREGNANCY, INCREASIG PELT SIZE IN FEMALE MINK, TREATING ARTHRITIS, OSTEOPOROSIS, ETC. THE COMPOUNDS OF FORMULA III ARE ADDITIONALLY USEFUL AS INTERMEDIATES IN THE PREPARATION, BY KNOWN METHODS, OF THE PHYSIOLOGICALLY ACTIVE AND THERAPEUTICALLY USEFUL 6-METHYL STEROIDS, SUCH AS MEDROXYPROGESTERONE ACETATE (6X-METHYL-17X-HYDROXY-4-PREGNENE-3,20-DIONE - 17 - ACETATE), DIMETHISTERONE (6X-METHYL -17B - HYDROXY - 17X -(1-PROPYNYL)-4-ANDROSTEN-3-ONE), METHYLPREDNIOLONE (6X-METHYL11B,17X,21-TRIHYDROXY-1,4-PREGNADIENE-3,20-DIONE), FLUOROMETHYLONE (6X-METHYL-9X-FLUORO-11B,17X-DIHYDROXY-1,4PREGNADIENE-3,20-DIONE),ETC.

United States Patent Olhce 3,642,840 Patented Feb. 15, 1972 3,642,840PROCESS FOR THE CONVERSION OF 3-ENOL ETHERS OF S-KETOeM-STEROIDSUNSUBSTI- TUTED AT C AND C TO THE CORRESPOND- ING 3-KETO-A -6-METHYLENECOMPOUNDS Verlan H. van Rheenen, Kalamazoo, Mich, assignor to The UpjohnCompany, Kalamazoo, Mich. No Drawing. Filed Nov. 19, 1969, Ser. No.878,218 Int. Cl. C(l7c 167/00 US. Cl. 260397.1 20 Claims ABSTRACT OF THEDISCLOSURE This invention relates to novel and general processes for theconversion of the 3-enol ethers (I) of 3-keto-A steroids, unsubstitutedat the 4 and 6 positions, of the androstane, 19-norandrostane, pregnane,19-norpregnane, stigmastane and spirostane series into the corresponding3-ketoA -6fl-(N,N-disubstituted) aminomethyl derivatives (II), andthence to their G-methylene counterparts (III). The compounds of FormulaIII have anabolic, androgenic, anti-fertility, anti-inflammatory andestrogenic activities, and are consequently useful in treating mammals,including humans, birds and other animals in those conditions and/ orailments Where such activities are desired. For example, in preventingpregnancy, increasing pelt size in female mink, treating arthritis,osteoporosis, etc. The compounds of Formula IH are additionally usefulas intermediates in the preparation, by known methods, of thephysiologically active and therapeutically useful 6-methyl steroids,such as medroxyprogesterone acetate(6u-methyl-17a-hydroxy-4-pregnene-3,2=0-dione 17 acetate),dimethisterone [6a-methyl 17B hydroxy 17a(l-propynyl)-4-androsten-3-one], methylpreclnisolone (6a-methyl-11B,17u,21-trihydroxy-1,4-pregnadiene-3,2O diorre), fluoromethylone(6a-methyl-9 a-fluoro-l 1,6, l7a-dihydroxy-l ,4- pregnadiene-3,20-dione)etc.

BRIEF SUMMARY OF THE INVENTION The present invention provides novelprocesses for the preparation of 3-keto-A -6-methylene (III) steroids ofthe androstane, 19-norandrostane, pregnane, 19-norpregnane, stigmastaneand spirostane series having in rings A and B of the steroid nucleus thestructure The novel processes for the production of the steroidalcompounds of Formula III (and intermediates therefor) are illustrativelyrepresented by the following sequence of A and B ring formulae:

wherein R is selected from the group consisting of alkyl of from onethrough twelve carbon atoms, hydroxylalkyl of from one through twelvecarbon atoms, cycloalkyl of from three through eight carbon atoms, arylof from six through fourteen carbon atoms, alkaryl wherein the arylmoiety is from six through fourteen carbon atoms and the alkyl group(s)substituted therein contain(s) from one through twelve carbon atoms,aralkyl wherein the alkyl moiety is from one through twelve carbon atomsand the aryl group(s) substituted therein contain(s) from six throughfourteen carbon atoms; in the compounds embraced by Formula II, R and Rare selected from the group consisting of alkyl of from one throughtwelve carbon atoms and aryl of from six through fourteen carbon atoms;in the compounds of Formulae IV, V and VI, R R and R are alkyl of fromone through twelve carbon atoms and X of Formulae IV and VI are selectedfrom the group consisting of halogen and alkylsulfate.

Androstane series is defined herein as those compounds containing thecarbon atoms skeleton:

in which each of the carbon-carbon linkages can be either single ordouble bonded, and which can have carbon, and/or other atoms assubstituents attached to the carbon atom skeleton.

ROJVV OQQ CH N o11-cH oH,-oHoH 12 17 20 22 23 2t 25\ 111 1 on,

Spirostane series is defined herein as those compounds containing thecarbon atom skeleton:

Examples of alkyl of from one through twelve carbon atoms are methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,undecyl and dodecyl and the isomeric forms thereof. Examples ofhydroxyalkyl of from one through twelve carbon atoms are hydroxymethyl,hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl,hydroxyheptyl, hydroxyoctyl, hydroxynonyl, hydroxydecyl, hydroxyundecyland hydroxydodecyl and the isomeric forms thereof. Examples ofcycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, Z-methylcyclobutyl, 2,3- diethylcyclobutyl,4-propylcyclobutyl, 3 cyclopentylpropyl, etc. Examples of aryl arephenyl, diphenyl, naphthyl, anthryl, etc. Examples of alkaryl are tolyl,xylyl, 2,4,6-triethylphenyl, 3-butylxylyl, S-hexyltolyl, 2-propyl-3-octyl-naphthyl, 2-pentyl-4-decylnaphthyl, 3-decyl-5- anthnyl, etc.,and the isomeric forms thereof. Examples of aral kyl are benzyl,phenethyl, a-phenylpropyl, anaphthylbutyl, fl-anthrylpropyl, etc., andthe isomeric forms thereof.

The 6-methylenation process of this invention is generally applicable tothe enolic derivatives of 3-keto-A steroids. It can be successfullyapplied to androstane, 19- norandrostane, 9 3,la-androstane, pregnane,19-norpregnane, 9,8,10tz-pregnane, spirostane, cholestane ergostane andstigmastane series compounds. The foregoing starting compounds cancontain the substituents listed below:

Hydroxyl groups and functional derivatives thereof in such positions ofthe steroid nucleus as 11, 12, 14, 15, 16 (including l-hydroxymethyl),17, 18, 20 and 21 (including the condensation products of16a,17a-glycols with carbonyl components),

Carbonyl groups such as at C C12, C1 C C C 19 and 20 Carbalkoxy groupsat C C and C or in the side chain,

Alkyl groups other than at C and C especially at C 7, 11, 16, 17 and 21,

Vinyl, allyl, alkynyl and haloalkynyl groups at C Methylene andethylidene groups at C C C and ur- 17 Lactone, ether and spiroketalresidues such as attached to C etheric groups at C and bridging C and Cspiroketal moieties such as are present in disogenone and spirostane,

Chlorine, bromine or fluorine substituents in rings C or D or in theside chain,

Unsaturated linkages at C C C C C and imo Ketol groups at Cu-Cm, Cw-Cn,Cry-C and C20- C21, Epoxides at C C and C C Corticord side chains whichcan be acylated, diacylated, condensed with carbonyl components such asformaldehyde or acetone (as 2,2-dimethoxypropane) or with estercomponents such as ethyl orthoformate, ethyl acetoacetate or otherfunctional derivatives thereof as are known to those skilled in thesteroid art.

The processes of this invention can be used for preparing the6-methylene counterparts (III) of the 6-(N,N- disubstituted) aminomethylcompounds (II) obtained from the corresponding 3-enol ethers (and acylderivatives thereof) (I), which are in turn derived from such 3-keto-4-enes as those that follow: testosterone, Z-methyltestosterone,

17 a-methyl-testosterone,

9 1 1)-dehydro-17a-methyltestosterone,

17a-propynyl-testosterone,

17a-acyloxyprogesterone,

9 (1 1 )-dehydro-17a-acyloxyprogesterone,

16-methyll 7a-acyloxyprogesterone,

9(11)-dehydro-16-methyl-17u-acyloxyprogesterone,

16-methylene-17ot-acyloxyprogesterone,

9(11)-dehydro-16-methylene-17a-acyloxy-progesterone,

17a-acyloxy-16-ethy1ideneprogesterone,

16a,17a-dimethylmethylenedioxyprogesterone,

9 11 )-dehydro-16a,l7a-dimethylmethylenedioxyprogesterone,

cortisone,

16-methylcortisone,

21-methylcortisone,

16-methylenec0rtisone,

16a-hydroxy cortisone and thereof,

hydrocortisone,

16-methylhydrocortisone,

21-methylhydrocortisone,

16-methylenehydrocortisone,

16 u-hydroxyhydrocortisone and the 16u,17oc)-21C6t0nid6 thereof,

17a,21-dihydroxypregna-4,9(11)-dione,3,20-dione,

16-methyl-17a,21-dihydroxypregna-4,9(1 1 )-diene- 3,20-dione,

2l-methyl-17u,2l-dihydroxypregna-4,9(11)-diene,

3,20-dione,

16-methylene-17a,21-dihydroxypregna-4,9(11)-diene- 3,20-dione,

16a-hydroxy-17a,2l-dihydroxypregna-4,9(1l)-diene- 3,20-dione and the(16,17)-acetonide thereof,

21-fluoro-17a-hydroxypregna-4,9 1 1)-diene-3,20-

dione and the (16,17)-acetonide thereof,

21-fluoro-17a-hydroxypregn-4-ene-3,1 1-20-trione and the (16, 17-acetonide thereof,

21-fluoro-11,17a-dihydroxypregn-4-ene-3,20-dione and the (16, 17-acetonide thereof,

21-hydroxypregna-4,17-dien-3-one,

11-oxo-21-hydroxypregna-4,l7-dien-3-one,

11,21-dihydroxypregna-4,17-dien-3-one,

9 1 1)-dehydro-21-hydroxypregna-4,17-dien-3-one,

3-oxo-pregna-4, 17 (20) -dien-2 l-oic acid (esters),

3,1 1-dioxopregna-4, 17 (20) -dien-2 l-oic acid (esters),

1 1-hydroxy-3-oxopregna-4, 17 (20)-dien-21-oic acid (esters),

9(11)-dehydro-3-oxopregna-4,17(20-dien-2l-oic acid (esters),

21-fiuoro-17a-acyloxyprogesterone, progesterone,

16-methylprogresterone,

l l-oxo progesterone,

9(11)-dehydroprogesterone,

21-methylprogesterone,

diosgenone,

17a-cyano-17fl-hydroxyandrost-4-en-3-one,

16-methyl-l6,l7-dehydroprogesterone,

16-cyano-progesterone,

l6-carbalkoxyprogesterone,

16-hydroxymethylprogesterone,

3-(3-oxo-17B-hydroxy-androst-4-en-l7a-yl) propionic acid,

2 l-fluoroprogesterone,

testoloacetone,

16-fluoro-corticoids,

l7a-hydroxyprogesterone,

3,1 1-dioxopregna-l,4, 17 (20)-trien-21-oic acid (esters),

1-methoxy-3, l 1-dioxopregna-4, 17 (20)-dien-21-oic acid (esters),

11a (and )8),

17a-dihydroxy progesterone,

1 l-oxo-17 a-hydroxyprogesterone,

3-oxo-11,8-21-dihydroxypregna-4,17(20)-diene (2l-acetate and3-oxo-l1,8,21-dihydroxypregna-1,4,l7(20)-triene (Zl-acetate) The9a-fluoro derivatives of the above llfi-hydroxy and ll-keto steroids.

It is well known in the steroid art that the introduction of a 6-methylgroup into a steroid molecule often imparts significant biologicalactivity to the thus methylated compound. Consequently, the o-methylenesteroids (III) prepared by the processes of this invention can beadvantageously converted to 6-methyl steroids, for example, by thehydrogenation method described in Tetrahedron 21, 1619.

The novel processes of this invention for preparing the 6-methylenesteroids of Formula III are described in sections A, B, C and D thatfollow.

(A) In carrying out the process of the present invention indicated bysteps I II- III in the flow-sheet, above, a compound of Formula I in asolvent (such as methanol, ethanol, propanol, isopropanol, t-butanol,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.) has a secondaryamine, formaldehyde (in the form of a 20 to 40% aqueous solution or asparaformaldehyde) and a strong acid added thereto and the reactionmixture maintained at ambient to reflux temperature, to give the3-keto-A -613- (N,'N-disubstituted) aminomethyl counterpart (11). Mixinga thus produced corresponding compound (H) With a strong acid, e.g.,hydrochloric, sulfuric, etc., yields a corresponding 6-methylene steroid(III). In this process R and R of Formula II are selected from the groupconsisting of alkyl of from one through twelve carbon atoms and aryl offrom six through fourteen carbon atoms, with the proviso that R and Rcannot both be alkyl.

The molar equivalents of secondary amine and formaldehyde must be equalto or greater than that of the starting steroid (I). The molecularratios of the compound of Formula I, the secondary amine andformaldehyde can be varied, molar ratios of about 1:1:1 up to thosewherein the amine and formaldehyde are about twenty times that of thestarting steroid compound (I), are satisfactory. Since formaldehyde isquite volatile and the reaction time relatively long, a large excess canbe added initially or additional formaldehyde added periodically duringthe course of the reaction.

The choice of solvent is dictated to some extent by the solubility ofthe starting enol ether (1) in that solvent. Alcohols such as thoselisted above can be employed, but polar aprotic solvents such astetrahydrofuran, dioxane and 1,2-dimethoxyethane are the most efiicient.

The secondary amine can be employed as the free base or, part may beadded as an acid salt (e.g., the hydrochloride, sulfate orp-toluenesulfonate) of the amine. Aromatic secondary amines such asdiphenylamine, methylnaphthylamine, N methylaniline, N-ethylaniline,N-methylp-toluidine, etc., can be employed.

The time required for the completion of the reaction depends upon suchfactors as the type of secondary amine, the particular starting steroid(1), its solubility, its relative amount in relation to secondary amineand formalehyde, thoroughness of mixing, solvent and the like. Thereforeit will be understood that the optimum reaction time will vary for eachset of reaction conditions. Ordinarily, the reaction will go tocompletion within from about 30 minutes to about five days.

After completion of the'reaction between I, the amine and formaldehyde,the thus formed 6,8-(N,N-disubstituted) aminomethyl product (II) isreadily isolated in high yield from the reaction mixture by conventionalmeans; for example, by evaporating the solvent, dissolving the residuein a solvent (such as benzene), extracting the solution with water, thendilute acid, neutralizing the acid phase with dilute alkali (e.g.,sodium carbonate) and extracting with a solvent such as methylenechloride, washing the methylene chloride layer with Water, then dryingand evaporating the methylene chloride to give a high yield of product(II). Mixing a thus produced corresponding compound of Formula 11 (atfrom about 0 C. to about 50 C.) with a strong acid (e.g., aqueous oralcoholic hydrochloric or sulfuric acid) precipitates a corresponding6-methylene compound (III), which can be recovered by filtration,centrifugation, etc.

(B) In the process of the present invention shown of I II IV III in theflow-sheet, above, the compounds of Formula II wherein R and R are alkylof from one through twelve carbon atoms, or together polymethylene, areprepared from the corresponding compounds of Formula I essentially asdescribed in A, above. However, such compounds of Formula II beforebeing converted to their 6-methylene counterparts (III) must first havethe nitrogen atom quaternized. This can be accomplished by reacting acompound of Formula II with an alkylating agent such as (a) an alkylhalide (e.g., methyl iodide, ethyl iodide, methyl bromide, ethylbromide, etc.) to form a corresponding quaternary halide of Formula IVor (b) a dialkyl sulfate (e.g., dimethyl sulfate, diethyl sulfate, etc.)to give a corresponding alkylosulfate of Formula IV. The preparation ofthe quarternary halides and alkylsulfates of Formula IV can be carriedout by reacting the 6/i-dialkylaminomethyl steroid (II) with the alkylhalide or dialkyl sulfate in an organic solvent such as methanol,isopropanol, t-butanol, acetone, ether, benzene, toluene, hexane,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., at temperaturesranging from ambient to reflux, with the reaction time and temperatureemployed depending on the solvent and alkylating agent used. Thecompounds of Formula IV are converted to the corresponding 6-methylenesteroids (III) by treatment with a base (e.g., aqueous sodium carbonate,potassium carbonate, sodium bicarbonate, sodium hydroxide, etc.),preferably at room temperautre or somewhat above, with the product (III)that precipitates being recovered by conventional means (e.g.,filtration).

(C) In carrying out the process of the invention indicated by thereaction sequence I II IV VI III in the flow-sheet, above, the compoundsof Formula II wherein R and R are alkyl of from one through twelvecarbon atoms, or together polymethylene, are prepared from thecorresponding compounds of Formula I essentially as described in A,above. The step II IV of the process (relating to the quaternizing ofthe nitrogen of the compounds of Formula II) is carried out in the samemanner as in B, above. The thus produced quaternary halides andalkylsulfates of Formula IV are subjected to enol etherification at the3-position of the steroid nucleus employing known procedures to yieldthe corresponding 3- alkoxy-A -steroids (VI), e.g., by heating at refluxfor several hours with a 2,2-dialkoxypropane (such as 2,2-dimethoxypropane, 2,2-diethoxypropane, etc.) with an acid such asp-toluenesulfonic acid, in a solvent such as dimethylformamide,methanol, etc. The enol ethers (VI) can also be produced by the reactionof the compounds of Formula IV at room temperature to about 50 C. forfrom about 1 to 3 hours with an alkyl orthoformate (such as methylorthoformate, ethyl orthoformate, etc.) with an acid (e.g.,p-toluenesulfonic acid, sulfuric acid, etc.) in a solvent such asdioxane, methanol, etc. Addition of water to the reaction mixturecontaining a thus produced compound of Formula VI precipitates thecrystalline 6- methylene product (III) which is isolated by filtration.

(D) In the process of the invention shown by I II- V III of theflow-sheet, above, the compounds of Formula II wherein R and R are alkylof from one through twelve carbon atoms, or together polymethylene, areprepared from the corresponding compounds of Formula I in the mannerdescribed in A, above. The N-oxides of Formula V are prepared from thecorresponding compounds of Formula II in the same manner as the alkylhalides and alkylosulfates embraced by Formula IV, by substitutinghydrogen peroxide for the alkylating agents employed in the step II IVin the processes described in sections B and C, above. The thus producedN-oxides (V) are converted to the corresponding compounds of Formula IIIby merely heating them (at about 70 for about 30 minutes) in an inertsolvent, such as methanol, tetrahydrofuran, etc., generally the one inwhich the compound of Formula V is prepared; the product (III) thatprecipitates is isolated by filtration. In those instances where theelimination of step V- III is diflicult, it can be facilitated by addinga basic substance such as a tertiary amine (e.g., trimethylamine,methylethylamine, methyldiphenylamine, etc.) or an alkali metalcarbonate, such as sodium carbonate, potassium carbonate, etc.

DETAILED DESCRIPTION It is to be understood that the invention is not tobe limited to the exact details of operation or exact compounds shownand described herein, as obvious modifications and equivalents will beapparent to one skilled in the art, and the invention is therefore to belimited only by the scope of the appended claims.

EXAMPLE 1 Methyl 6-mcthylene-3,11-dioxo-4,17(20)-pregnadien- 2l-oate(III) (a) Methyl 65 (N phenyl N methylaminomethyl) 3,11 dioxo 4,17(20)pregnadicn 21 oate (II).-To 60 ml. of tetrahydrofuran containing 6.45 g.of methyl 3 methoxy 3,5,17(20) pregnatrien lloxo-21-oate (I) is added 6ml. of 37% Formalin, 2.0 ml. N-methyl aniline and 100 mg. ofp-toluenesulfonic acid. This mixture is stirred at room temperature forabout 45 minutes and poured into very dilute sodium carbonate. Themixture is extracted with methylene chloride, dried over sodium sulfateand evaporated in vacuo to give a high yield of methyl 6b (N phenyl Nmethylaminomethyl)-3,11-dioxo-4,17(20)-pregnadien-21-oate (II).

Using the procedure of (a), above, but substituting other secondaryamines, such as (1) N-ethyl aniline,

(2) Diphenylamine,

(3) N-methyl-p-toluidine,

(4) N-ethyl-p-toluidine,etc., yields, respectively,

(1) Methyl 6,8-(N-ethyl-N-phenylaminomethyl)-3,l1-dioxo-4,17(20)-pregnadien-2l-oate (II),

(2) Methyl 6,8-N,N-diphenylaminomethyl-3,1l-dioxo-4,17(20)-pregnadien-21-oate (II),

(3) Methyl 613-(N-methyl-N-p-toluylaminomethyl)-3,1l-dioxo-4,l7(20)-pregnadien-2l-oate (II).

(4) Methyl613-(N-ethyl-N-p-toluylaminomethyl)-3,1ldioxo-4,17(20)-pregnadiene-21-oate(II), etc.

(b) Methyl 6 methylene 3,11 dioxo 4,17(20)- pregnadien-Zl-oate (III).5g. of methyl 6,8-(N-phenyl- N methylaminomethyl) 3,ll dioxo 4,17()pregnadien-2l oate (11), prepared as in (a), above is dissolved in 40ml. of 6 N hydrochloric acid. After about 10 min- EXAMPLE 26-methylene-17a-hydroxy-4-pregnene-3,20-dione (III) Following theprocedure of Example 1 but substituting3-methoxy-17a-hydroxy-3,5-pregnadien-20-one (I) as starting materialyields (a)6fl-(N-methyl-N-phenylaminomethyl)17u-hydroxy-4-pregene-3,20-dione (II)and (b) 6 methylene 17a hydroxy 4 pregnene 3,20- dione (III).

EXAMPLE 3 Methyl 6-methylene-3,1 1-dioxo-1,4, 17 (20) -pregnatrien- 2l-oate (III) Following the procedure of Example 1 but substitutingmethyl 1a,3 dimethoxy 3,5,17(20) pregnatrien 11- one 21-oate (I) yields(a) 65 (N methyl N phenylaminomethyl) 3,11 dioxo 1,4,17(20)pregnatriene- 21-oate (II) and (b) methyl-6 methylene 3,11 dioxo-1,4,17(20)-pregnatrien-21-oate (III).

EXAMPLE 4 6-methylene-17/3-hydroxy-17u-methyl-4,9(l1)-androstadien-3-one (III) Following the procedure of Example 1 butsubstituting 3 ethoxy 17B hydroxy 17oz methyl 3,5,9(11)- androstatriene(I) yields (a) 6,8 (N methylanilinomethyl) 1713 hydroxy 17a methyl4,9(11) androstadien 3 one (II) and (b) 6 methylene 17Bhydroxy-17a-methyl-4,9(11)-androstadien-3-one (III) EXAMPLE 56-methylene-9a-fiuoro-1 1/3,17a,21-trihydroxy-4- pregnene-3,20-dione21-acetate (III) Following the procedure of Example 1 but substituting 3anthryloxy 9a fluoro 11fl,l7a,21 trihydroxy 3,5- pregnadien-ZO-one17-acetate (I) and N-methyl-p-toluidine yields (a) 6,5 (N methyl ptoluidinomethyl)- 9oz fluoro 11/3,l7a,21 trihydroxy 4 pregnene 3,20-dione 21-acetate (III) and (b) 6 methylene 9a fluoro- 11B,17a,21trihydroxy 4 pregnene 3,20 dione 21- acetate (III).

EXAMPLE 6 6-methylene-4-estrene-3,17-dione (III) Following the procedureof Example 1 but substituting 3 methoxy 3,5 estradien 17 one (I) anddiphenylamine, yields (a) 613 diphenylaminomethyl 4 estrene- 3,17-dione(II) and (b) 6-methylene-4-estrene-3,l7- dione (III).

EXAMPLE 7 6-methylene-9 3,10a-pregn-4-ene-3,20-dione (111) Following theprocedure of Example 1 but substituting 3 ethoxy 95,100 pregna 3,5 dien2O one (I) yields (a) 6 3 (N methylanilinomethyl) 95,1011- pregn 4 ene3,20 dione (II) and 6 methylene- 95,10a-pregn-4-ene-3,20-dione (III).

EXAMPLE 8 6-methylene-17-oxa-D-homo-4-androstene-3,l7- dione (III)Following the procedure of Example 1 but substituting 3 ethoxy 17 oxa Dhomo 3,5 androstadien 17- one (I) and ethylphenylamine, yields (a) 6Bethylphenylaminomethyl 17 oxa D homo 4 androstene- 3,17-dine (II) and(b) 6-methylene-l7-oxa-D-homo-4- androstene-3,l7-dione (III).

EXAMPLE 9 6,16-dimethylene-17a-hydroxy-4-pregnene-3,20-dione 17-acetate(III) Following the procedure of Example 1 but substituting 3 isopropoxy170a hydroxy 16 methylene 3,5- pregnadien-ZO-one 17-acetate (I) andN-methyl-p-toluidine yields (a) 6B (N methyl p toluidinomethyl)- 17ozhydroxy l6 methylene 4 pregnene 3,20- dione 17-acetate (II) and6,l6-dimethylene-17m-hydroxy- 4-pregnene-3,20-dione 17-acetate (III).

EXAMPLE 6-methylene-17a-hydroxy-4-pregnene-3,20-dione 17-acetate (III)Following the procedure of Example 1 but substituting 3 propoxy 17cchydroxy 3,5 pregnadien one 17-acetate (I) yields (a) 6B (N phenyl Nmethylaminomethyl) 17a hydroxy 4 pregnene 3,20 dione 17-acetate and (b)6-methylene-l7a-hydroxy-4-pregnene- 3,20-dione l7-acetate (III).

EXAMPLE l1 6-methylene- 1 7a-hydroxy-4-pregnene-3,20-dione 17-acetate(III) (a) 6/3-piperidinomethyl 17a-hydroxy-4-pregnene-3, 20-dione17-:ace'tate (II).To a solution of 3 g. of17ahydroxy-3-methoxy3,S-pregnadien-ZO-one 17-acetate (I) in ml. oftetrahydrofuran, 1.5 ml. of piperidine, 0.5 ml. of 37% Formalin and 10mg. of p toluenesulfonic acid is added. This solution is refluxed on asteam bath for about 100 hours. During the reflux period, incrementstotalling 3 ml, of Formalin and 2 ml. of piperidine are added. Thetetrahydrofuran is evaporated and the resulting residue extracted withbenzene. The benzene solution is extracted with water and then with 0.2N sulfuric acid. The acid phase is neutralized with dilute sodiumcarbonate solution and then extracted with methylene chloride. Themethylene chloride layer is washed with dilute hydrochloric acidsolution, dilute sodium carbonate solution, dried and the solventevaporated to give a high yield of6B-piperidinomethyl-17a-hydroxy-4-pregnene-3, ZO-dione 17-acetate (II).

Following the procedure of (a), above, of Example 11 but using 1.5 g. ofp-toluenesulfonic acid instead of 10 mg. thereof, the reaction producing6B-piperidinomethyl- 17a-hydroxy-4-pregnene-3,20-dione 17-acetate (II)is complete in 3 hours.

Following the procedure of (a), above, of Example 11 and the paragraphthereafter but substituting other secondary amines, such as (l)morpholine,

(2) 2-propy1piperidine,

(3 2,6-dimethy1piperidine,

(4) 2-ethyl-fi-methylpiperidine,

(5) pyrrolidine,

(6) 3-ethylpyrrolidine,

(7) 2,4-dimethylpyrrolidine,

(8) dimethylamine,

(9) ethylbutylamine, etc., yields, respectively,

( 1 6 ,B-morpholinomethyl-17u-hydroxy-4-pregnene-3,

20-dione 17-acetate (II),

(2) 6B(2-propyl piperidinomethyl)-17a-hydroxy-4- pregnene-3,20-dione17-acetate (II),

(3 6,8-(2,6-dimethy1 piperidinomethyl) -17a-hydroxy-4-pregnene-3,20-dione 17-acetate (II),

(4) 6fl-(2-ethyl-6-methylpiperidinomethyl)-17a-hydroxy-4-pregnene-3,20-dione 17-acetate (II),

(5) GB-pyrrolidinomethyl-17a-hydroxy-4-pregnene-3,

ZO-dione 17-acetate (II),

(6) 6p-(3-ethylpyrrolidinornethyl)-17ot-hydroxy-4- pregnene-3,20-dione17-acetate (II),

10 (7) 6 3- (2,4-dimethylpyrrolidinomethyl) -17u-hydroxy-4-pregnene-3,20-dione 17-acetate (II), (8)6,8-dimethylaminomethyl-l7a-hydroxy-4-pregnene- 3,20-dione 17-acetate(II), (9) 6/3-ethylbutylaminomethyl-l7u-hydroxy-4-pregnene 3,20-dione17-acetate (II), etc.

(b) 6fl-pi-peridinornethyl-l7a-hydroxy-4-pregnene-2,20- dione 17-acetatemethiodide (IV) 17-acetate methobromide (IV) and substituting dimethylsulfate for methyl iodide yields the corresponding methosulfate.

(c) 6-methylene-17a-hydroxy-4-pregnene-3,20- dione 17-acetate (III) Theresidue containing the methiodide (1V) obtained in (b), above, isdissolved in 20 m1. of 1 N sodium carbonate solution and the resultingsolution allowed to stand at room temperature for about 16 hours. The

crystals of 6-methylene-l7ot hydroxy-4-pregnene-3,20- dione 17-acetate(III) that formed were separated by filtration.

EXAMPLE 12 6-methy1ene- 1 1B,1704,21-trihydroxy-4-pregnene- 3,20-dione17-valerate (III) Following the procedure of Example 11 and theparagraphs thereafter but substituting 1a,3-dibIlt0Xy-l1fi,l7oc,21-trihydroxy-3,5-pregnadien-20-one 17-valerate (I) and 2-propylperidinefor the starting material (I) and secondary amine employed therein,yields (a) 613-(2-propylpiperidinomethyl) -1a-butoxy 1 1B, 17 11,2l-trihydroxy-4- pregnene-3,20-dione 17-valerate (II), (b) thecorresponding methiodide (IV) and (c) 6-methylene-11fl,17a,21-trihydroxy-l,4-pregnadiene-3,20-dione 17-valerate (III).

EXAMPLE l3 Ethyl 6-methylene-3-keto-1,4,17 (20) -pregnatrien 21-oate(III) Following the procedure of Example 12 but substituting3-cyclopentyloxy 1,3,5,17(20) pregnateraene-Zlethyl-oate (I) and2,6-dimethylpiperidine yields (a) 613- (2,6-dimethylpiperidinomethyl)3-keto-1,4,17(20)-pregnatrien-Zloate (II), (b) the correspondingmethiodide (1V) and (c) ethyl6-methylene-3-keto-l,4,l7(20)-pregnatrien-Zl-oate (III).

EXAMPLE 14 6-methylene-l7oc,2l-dihydroxy-1,4-pregnadiene-3, 11,20-trione21-butyrate (III) Following the procedure of Example 12 but substituting3-(fl-hydroxypropoxy)-17a,21-dihydroxy-1,3,5-pregnatriene-11,20-dione21-butyrate (I) and diethylamine, yields (a)6-diethylaminomethyl-170:,21 hydroxy-l,4- pregnadiene-3,11,20-trioneZI-butyrate (II), (b) the corresponding methiodide (IV) and (c)6-methylene-17a, 21-dihydroxy-1,4-pregnadiene-3,1 1,20-trione21-butyrate (III).

EXAMPLE 15 6-methy1ene-17a-methyl-17B-hydroxy-4-androsten- 3-one17-propionate (III) Following the procedure of Example 12 butsubstituting 3-benzyloxy-17a-methyl -hydr0xy-3,5-androstadiene17-pr0pionate (I) and pyrrolidine, yields (a) 6,8-pyrrolidinomethyl-17a-methyl 17fl-hydroxy-4-androsten- 3-one17-propionate (III), (b) the corresponding metho- 11 bromide (IV) and(c) 6-methylene-17a-methyl-l7B-hydroxy-4-androsten-3-one l7-propionate(IH).

EXAMPLE 16 6-methylene-17a-hydroxy-4-pregnene-3,20-dione (III) Followingthe procedure of Example 12 but substituting3-ethoxy-17a-hydroxy-3,5-pregnadien-20one (I) and 3-ethylpyrrolidine,yields (a) 69-(3-ethylpyrrolidinomethyl)-17a-hydroxy-4-pregnene-3,20-dione (I), (b)the corresponding methiodide (IV) and (c)6-methylene-17ahydroxy-4-pregnene-3,20-dione (III).

EXAMPLE 17 6-methylene-4-pregnene-3,1 1,20-trione (III) Following theprocedure of Example 12 but substituting 3 naphthoxy 3,5 pregnadiene11,20-dione (I) and 2,4 dimethylpyrrolidine (II), yields (a) 618(2,4-dimethylpyrrolidinomethyl) 4 pregnene 3,11,20-trione (II), (b) thecorresponding methiodide (IV) and 6- methylene-4-pregnene-3,l1,20-trione(III).

EXAMPLE 18 6-methylene-4-androstene-3,17-dione (III) Following theprocedure of Example 12 but substituting3-phenoxy-3,5-androstadien-17-one (I) and ethylbutylamine, yields (a) 6Bethylbutylaminomethyl 4 androstene 3,17 dione (II), (b) thecorresponding methiodide (IV) and (c) 6-methylene-4-androstene-3,17-dione (III).

EXAMPLE 19 Methyl 6-methylene-3,1 1-dioxo-1,4,17(20)- pregnadien-Zl-oate(III) 6-methylene-1 7a-ethynyl- 17 fi-hydroxy-4- androsten-3-one (III)Following the procedure of Example 11 but substituting 3 hexyloxy 17ethynyl 17/3-hydroxy-3,5-androstadiene (I) and 2 propylpiperidine,yields (a) 65 (2- propylpiperidinomethyl) 171x ethynyl 17 3 hydroxy-4-androsten-3-one (II), (b) the corresponding methosulfate (IV) and (c)6 methylene 17a ethynyl-17fihydroxy 4 androsten 3 one (III).

EXAMPLE 21 6-methylene-25D-spirosta-4-en-3-one (III) Following theprocedure of Example 11 but substituting 3 (3 propylphenoxy) 25Dspirosta 3,5 diene (I) and 2,6 dimethylpiperidine, yields (a) 6,6 (2,6-dimethylpiperidinomethyl) 25D spirosta 4-en-3-one (II), (b) thecorresponding methosulfate (IV) and (c)6-methylene-25D-spirosta-4-en-3-one (III).

EXAMPLE 22 6-methylene-l 1 B,17a,21-trihydroxy-4-pregnene- 3,20-dione17a,21-acetonide (III) Following the procedure of Example 11 butsubstituting 3-phenoxy llfl,l7oc,2l trihydroxy 3,5-pregnadien- 20 one17,21 acetonide (I) and 2-ethyl-6-methylpiperidine, yields (a) 6B (2ethyl 6 methylpiperidinomethyl) l1 3,l7a,2l trihydroxy 4 pregnene 3,20-dione 170:,21 acetonide (II), (b) the corresponding methosulfate (IV and(c) 6 methylene 1l/3,l7a,21-

12 trihydroxy 4 pregnene-3,20-dionc 17a,2l-acetonide (III).

EXAMPLE 23 6-methylene-l7fl-hydroxy-l7a-vinyl-1,4- androstadien-3-one(III) Following the procedure of Example 11 but substituting 3 butoxy17f! hydroxy 17oz vinyl-1,3,5-androstatn'ene (I) and pyrrolidine, yields(a) 6fi-pyrrolidino-17/3- hydroxy 17a vinyl 1,4-androstadien-3-one (II),(b) the corresponding methosulfate (IV) and (c) 6 methylene 17/3 hydroxy17 vinyl-1,4-androstadien-3-one (III).

EXAMPLE 24 6-methylene-l7a,21-methoxymethylenedioxy-4-pregnene-3,11,20-trione (III) Following the procedure of Example 11but substituting 3 (3 butylphenoxy) :,21 methoxymethylenedioxy- 3,5pregnadiene 11,20-dione (I) and 3-ethylpyrrolidine, yields (a) 6B (3ethylpyrrolidinomethyl) 1711,21- methovymethylenedioxy 4 pregnene 3,1120 trione (II), (b) the corresponding methosulfate (IV) and (c) 6methylene 170:,21 methoxymethylenedioxy 4- pregnene-3,ll,20-trione(III).

EXAMPLE 25 6-methylene-17ot-hydroxy-4-pregnene-3,20- dione 17-acetate(III) (a) 6fl-piperidinomethyl-17a-hydroxy-4-pregnene- 3,20-dione17-acetate (II) This compound and others of Formula II are prepared inthe manner described in (a) of Example 11, above, employing 170;hydroxy-3-methoxy-3,5-pregnadien-20- one 17-acetate (I) as startingmaterial. Other 3-keto- A -6fl-(N,N-disubstituted) aminomethylcompounds, e.g., morpholinomethyl, pyrrolidinomethyl, etc., can beprepared in the manner described in Example 11, above.

(b) 6,8-piperidinomethyl-17u-hydroxy-4-pregnene-3,20- dione 17-acetatemethosulfate (IV) To 2 g. of 6l3-piperidinomethyl 171x hydroxy-4-pregnene 3, 20 dione 17 acetate (II) obtained as in (a), above, in 30ml. of methanol, 5 ml. of dimethyl sulfate is added and the solutionheated at about 45 C. for about 2 hours, to yield 613piperidinomethyl-17ahydroxy 4 pregnene 3,20 dione l7-acetatemethosulfate (IV).

(c) 6fl-piperidinomethyl-l7a-hydroxy-3-methoxy-3,5- pregnadien-20-one17-acetate methosulfate (VI) To the methosulfate (IV) prepared in (b),above, 5 ml. of trimethylorthoformate and 0.5 ml. of concentratedsulfuric acid is added and the mixture heated at about 45 C. for about2.5 hours to yield 6fl-piperidinomethyl- 17oz hydroxy 3 methoxy 3,5pregnadien-ZO-one 17-acetate methosulfate (VI).

(d) 6-methylene-17a-hydroxy-4-pregnene-3,20- dione 17-acetate (III) Tothe 3-enol ether (VI) produced in (c), above, 10 ml. of water is addedand crystals of 6-methylene-l7ahydroxy 4 pregnene 3,20 dione l7 acetate(III) precipate and are isolated by filtration.

EXIAMPLE 26 6-methylene-4-pregnen-18-oic acid (18-20) lactone-3-one(III) Following the procedure of Example 25 but substituting 3(2-propylnaphthoxy)-3,5,-pregnadien-18-oic acid (18-20) lactone (I) anddipropylamine, yields (a) 6 6 (di N propylaminomcthyl)-4-pregncnc-l8-oicacid (l8-20) lactonc-3-one (II), (b) the corresponding methosulfate(IV), (c) the corresponding 3-enoy1 ether 13 (VI) and (d)6-methylene-4-pregnene-18-oic acid (18- 20) lactone-3-one (III).

EXAMPLE 27 6-methylene-l6u,l7u-isopropylidene-dioxy-4-pregnene-3,20-dione (III) Following the procedure of Example 25 but substituting3 tolyloxy 16a,17a-isopropylidenedioxy-3,5- pregnadiene-ZO-one (I) anddimethylamine, yields (a) 6,8 dimethylaminomethyl 16a,l7u-isopropylidenedioxy- 4-pregnene-3,20-dione (II), (b) thecorresponding methosulfate (IV), (c) the corresponding 3-enol ether (VI)and (d) 6-methylene-16oz,17a-isopropylidenedoxy-4- pregnene-3,20-dione(III).

EXAMPLE 28 6-methylene-16-methyl-4, 16-pregnadiene-3,20-

' dione (HI) Following the procedure of Example 25 but substituting 3methoxy 16-methyl-3,5,l6-pregnatrien-20- one (I), yields (a)6,8-piperidinomethyl-16-methyl-4,16- pregnadiene-3,20-dione (II), (b)the corresponding methosulfate (IV), (c) the corresponding 3-enol etherand (d) 6 methylene-16-methyl-4,l6-pregnadiene-3,20- dione (III).

EXAMPLE 29 6-methylene-l7fi-hydroxy-l9-nor-4-androsten-3-one17-propionate (III) Following the procedure of Example 25 butsubstituting 3 propoxy 17 8 hydroxy l9-nor-3,5-androstadiene17-propionate (I) and 2-propylpiperidene, yields (a) 6 3 (2propylpiperidinomethyl)-17B-hydroxy-19- nor-4-androsten-3-onel7-pr0pionate (II), (b) the corresponding methosulfate (IV, (c) thecorresponding 3-enol ether (VI) and (d)6-methylene-17fl-hydroxy-19-nor-4- andrstene-3-one 17-propionate (III).

EXAMPLE 3O 6-methylene-20B-hydroxy-4apregnene-3-one 20- propionate (III)Following the procedure of Example 25 but substituting 3 decoxy 205hydroxy-3,5-pregnadiene 20- propionate (I) and 2,6-dimethylpiperidine,yields (a) 65- (2,6 dimethyl)piperidinomethyl 20,6 hydroxy 4-pregne-3-one ZO-propionate (II),- (b) the corresponding methosulfate(IV), (c) the corresponding 3-enol ether (VI) and (d)6-methylene-2OB-hydroxy-4-pregnene-3-one 20-propionate (III).

EXAMPLE 3 l.6-methylene-l7a-hydroxy-4-pregnene- 3,20-dione l7-acetate(III) (a) 6,8-piperidinomethyl-l7u-hydroxy-4-pregnene- 3,20-dionel7-acetate (II) This compound and others of Formula II are prepared inthe manner described in (a) of Example 11, above, employing 17a hydroxy3-methoxy-3,S-pregnadien-ZO- one l7-acetate (I) as starting material.Other 3-keto-A 6B-(N-disubstituted) aminomethyl compounds, e.g.,morpholinomethyl, pyrrolidinomethyl, etc., can be prepared in the mannerdescribed in Example 11, above.

(b) 6fl-piperidinomethyl-l7u-hydroxy-4-pregnene-3,20- dione 17-acetatemethiodide (IV) 14 (c) 6fi-piperidinomethyl-17a-hydroxy-3-methoxy-3,5-pregnadien-ZO-one l7-acetate methiodide (IV) To the methiodide (IV)prepared in (b), above, 5 ml. of trimethylorthoformate and 0.5 ml. ofconcentrated sulfuric acid is added and the mixture stirred at about 45C. for about 2.5 hours to yield6fi-piperidinomethyl-l7a-hydroxy-3-methoxy-3,5 pregnadien 20 onel7-acetate methiodide (VI).

((1) 6-methylene-l7a-hydroxy-4-pregnene-3,20-dione l7-acetate (III) Tothe 3-enol ether (VI) produced in (c), above, 10 m1. of water is addedand crystals of 6-methylene-l7u-hydroxy-4-pregnene-3,20-dione 17-acetate(III) precipitate and are isolated by filtration.

EXAMPLE 32 6-methylene-l7a,21a-dihydroxy-1 lB-formyloxy-4-pregnene-3,20-dione 21-acetate (III) Following the procedure of Example31 but substituting 3 octoxy 170;,2l-dihydroxy-llfi-formyloxy-3,5-pregnadien-20-one 2l-acetate (I) and methyl ethyl amine, yields (a)6 3-(methyl ethyl aminornethyl)-l7a,2l dihydroxy formyloxy4-pregnene-3,20-dione 2lacetate II), (b) the corresponding methiodide(IV), (c) the corresponding 3-enol ether (VI) and (d) 6-methylene :,21dihydroxy 115 formyloxy-4-pregnene- 3,20-dione l7-acetate (III).

EXAMPLE 33 6-methylene-1 1B, 17a,2 l-trihydroxy-1,4-pregnadiene-3,20-dione 17,21-diacetate (III) Following the procedure of Example 3but substituting 3 methoxy 11,3,l7a,2l trihydroxy-1,3,5-pregnatrien-20-one 17,2l-diacetate (I) and pyrrolidine, yields (a) 6,8-pyrrolidinomethyl 11B,l7oc,21 trihydroxy-l,4-pregnadiene-3,20-dione l7,Zl-diacetate (II), (b) the corresponding methiodide (IV), (c) thecorresponding 3-enol ether (VI) and (d)6-methylene-1l,B,l7u,2l-trihydroxy-l,4- pregnadiene-3,20-dione17,21-diacetate (III).

EXAMPLE 34 6-methylene-2a,methyll 1B,17,2l-trihydroxyl pregnene-3,20-dione 2 l-acetate (III) Following the procedure of Example 31 butsubsituting 3 methoxy Za-methyl-ll.,B-17u,2l-trihydroxy3,5-pregnadien-20-one 2l-acetate (I) and 3-ethylpyrrolidine, yields (a)6/8-(3-ethylpyrrolidinomethyl)Jot-methylll,l7a,2l trihydroxy4-pregnene-3,20-dione 21 acetate (II), (b) the corresponding methiodide(IV), the corresponding 3-enol ether (VI) and (d) 6-methylene-2amethyl1lfl,l7a,21 trihydroxy 4 pregnene-3,20-dione Zl-acetate (III).

EXAMPLE 35 .-6-methylene-17a-hydroxy-4-pregnene- 3,20-dione 17-acetate(IV) (a) 6/3-piperidinomethyl-l7a-hydroxy-4-pregnene-3,20- dione17-acetate (II) This compound and others of Formula II are prepared inthe manner described in Example 11, above, employing 17a hydroxy3-methoxy-3,5-pregnadien-20-one l7- acetate (1) as starting material.Other 3 keto-A -6B-(N- disubstituted) aminomethyl compounds, e.g.,morpholinomethyl, pyrrolidinomethyhete, can be prepared in the mannerdescribed in Example 11, above.

(b) 6 3-piperidinomethyl-l7a-hydroxy-4-pregnene-3,20- dione 17-acetateN-oxide (V) To 900 mg. of 6/3 piperidinomethyl-l7a-hydroxy-4-pregnene-3,20-dione l7-acetate (II), prepared as in (a), above, in 10ml. of methanol, 3 ml. of 30% hydrogen peroxide in 5 ml. of water isadded and the mixture stirred at room temperature for about 72 hours toyield 6B piperidinomethyl-l7a-hydroxy-4-pregnene-3,20-dione 17-acetateN-oxide (V).

(c) G-methylene-17a-hydroxy-4-pregnene-3,20-dione 17- acetate (IV) TheN-oxide -(V) produced in (b), above, is warmed for from about 70 C. toabout 75 C. for about 30 minutes, with crystals of 6methylene-17a-hydroxy-4- pregnene-3,20-dione 17-acetate (III)precipitating and being isolated by filtration.

EXAMPLE 36 6-methylene-l 1/3, l7a-dihydroxy-21-methyl-4-pregnene-3,20-dione (III) Following the procedure of Example 35 but substituting3 ethoxy 11B,17a-dihydroxy-2l-methyl-3,5-pregnadien one (I) and2,4-dimethylpyrroline, yields (a) 6B (2,4dimethylpyrrolidinomethyl)-11B,17u-dihydroxy-21-methyl-4-pregnene-3,20-dione(II), (b) the corresponding N-oxide (V) and (c)6-methylene-11/3,17-dihydroxy-21-methyl-4-pregnene-3,20-dione (III).

EXAMPLE 37 6-methylene-2l-fluoro-17a-hydroxy-4-pregnene-3,20- dione17-acetate (111) Following the procedure of Example 35 but substituting3 methoxy-21-fiuoro-17a-hydroxy-3,5-pregnadien-20-one 17 acetate (I) anddiethylamine, yields (a) 6,B-diethylaminomethyl 21fluoro-17a-hydroxy-4-pregnene-3,20- dione 17-acetate (II), '(b) thecorresponding N-oxide (V) and (c) 6 methylene-17-acetate17a-hydroxy-21-fluoro- 4-pregnene-3,20-dione 17-acetate (III).

EXAMPLE 38 6-methylene-l6-methyl-14,16-pregnatriene-3,20-dione (III)Following the procedure of Example 35 but substituting3-ethoxy-16-methyl-1,3,5,16-pregnatetraen-20-one (I) and pyrrolidine,yields (a) 6,3 pyrrolidinomethyl-16-n1ethyl-1,4,16-pregnatriene-3,20-dione (II), (b) the corresponding N-oxide (V)and (c) 6 methylene-16-methyl-4,l6- pregnadiene-3,20-dione (III).

EXAMPLE 39 6-methylene-19-norl7a-ethynyl-17fl-hydroxy-4- androsten-3-one(III) Methyl 6-methylene-3,l1-dioxo-4,17(20)-pregnadien-2loate (III)Following the procedure of Example 35 but substituting methyl 3(fl-hydroxyethoxy)-3,5,17(20)-pregnatrien-l1- oxo-21 oate (I) andethylbutylamine, yields (a) methyl 613 ethylbutylaminomethyl3,11-dioxo-4,17(20)-pregnadien-21-oate (II), (b) the correspondingN-oxide (V) and (c) methyl6-methylene-3,11-dioxo-4,17(20)-pregnadien-21-oate (III).

EXAMPLE 41 6-methylene-4-androsten-l7-one (III) Following the procedureof Example 35 but substituting 3 naphthoxy-3,5-androstadien-l7-one (I)and 3-ethylpyrrolidine, yields (a) 6/3(3-ethylpyrrolidinomethyl)-4-androsten-l7-one (II), (b) thecorresponding N-oxide (V) and (c) 6-methylen-4-androsten-l7-ene (III).

1 6 EXAMPLE 42 6-methylene- 1 701,2 1-dihydroxy-4,9( 1 1)-pregnadien-20-one 21-acetate (III) Following the procedure of Example 35 butsubstituting 3 phenoxy 17a,21-dihydroxy-3,5,9(1l)-pregnatrien-20- one21-acetate (I) and morpholine, yields (a)6fi-morpholinomethy1-17a,21-dihydroxy-4,9(1 1)-pregnadien-20- one21-acetate (II), (b) the corresponding N-oxide (V) and (c) 6methylene-17u,21-dihydroxy-4,9(11)-pregnadien-ZO-one 21-acetate (III).

EXAMPLE 43 6-methylene-l7fi-hydroxy-17a-vinyl-4-androstene 17-propionate (III) Following the procedure of Example 35 but substituting3 propoxy-17fl-hydroxy-17a-vinyl-3,S-androstadiene-17- propionate (I)and 2,6-dimethylpiperidine, yields (a) 6B- (2,6-dimethylpiperidinomethyl) 17fi-hydroxy-17a-vinyl- 4-androstene 17-propionate(II), (b) the corresponding N-oxide (V) and (c)6-methylene-1713-hydroxy-17a-vinyl- 4-androstene 17-propionate (III).

EXAMPLE 44 6-methylene-17a,2l-dihydroxy-4-pregnene-11,20-dione17,21-diacetate (III) Following the procedure of Example 35 butsubstituting 3 (t3 ethoxyethoxy)-17a,2l-dihydroxy-3,5-pregnadien-11,20-dione 17,21-diacetate (I) and dimethylamine, yields (a) 6Bdimethylaminomethyl-17a,21-dihydroxy-4-pregnene-11,20-dione17,21-diacetate (II), (b) the corresponding N-oxide (V) and (c)6-methylene-17a,21-dihydroxy- 4-pregnene-1l,20-dione 17,2l-diacetate(III).

I claim:

1. A process for the production of a steriod compound having in rings Aand B of the steroid nucleus the structure PJH: III

which comprises the steps of (1) mixing a corresponding steroid compoundhaving in rings A and B of the steroid nucleus the structure wherein Ris selected from the group consisting of alkyl of from one throughtwelve carbon atoms, bydroxyalkyl of from one through twelve carbonatoms, cycloalkyl of from three through eight carbon atoms, aryl of fromsix through fourteen carbon atoms, alkaryl wherein the aryl moiety itsfrom six through fourteen carbon atoms and the alkyl group(s)substituted therein contain(s) from one through twelve carbon atoms,aralkyl wherein the alkyl moiety is from one through twelve carbon atomsand the aryl group(s) substituted therein contain(s) from six throughfourteen carbon atoms, with formaldehyde and a compound of the formulawherein R and R are selected from the group consisting of alkyl of fromone through twelve carbon atoms and aryl of from six through fourteencarbon atoms, with the proviso that R and R cannot both be alkyl, toyield a corresponding compound having in rings A and B of the steroidnucleus the structure wherein R and R have the same meaning as above;

(2) mixing a thus produced corresponding compound resulting from step(1) with a strong acid to yield a corresponding compound of Formula HI,above.

2. A process in accordance with claim 1 wherein the compound of FormulaIII is methyl 6-methylene-3,11- dioxo-4,17(20)-pregnadien-2l-oate, thecompound of Formula I is methyl11-oxo-3-methoxy-3,5,l7(20)-pregnatrien-Zl-oate, and the compound ofFormula II is methyl GB-(N-phenyl N methylaminomethyl)-3,1 1-dioxo-4, 17(20) -pregnadien-2l-oate.

3. A process for the preparation of a steroid compound having in rings Aand B of the steroid nucleus the structure Hz III which comprises mixingwith a strong acid a corresponding steroid compound having in rings Aand B of the steroid nucleus the structure lHzN 1R2 II wherein R and Rare selected from the group consisting of alkyl of from one throughtwelve carbon atoms and aryl of from six through fourteen carbon atoms,with the proviso that R and R cannot both be alkyl.

4. A process in accordance with claim 3 wherein the compound of FormulaIII is methyl 6-methylene-3,11- dioxo-4,17(20)-pregnadien-21-oate andthe compound of Formula II is methyl6,9-(N-phenyl-N-rnethylaminomethyl-3,11-dioxo-4,17 (20-pregnadien-21-oate.

5. A process for the production of a steroid compound having in rings Aand B of the steroid nucleus the structure in, which comprises the stepsof (1) mixing a corresponding steroid compound having in rings A and Bof the steroid nucleus the structure Ron-W wherein R is selected fromthe group consisting of alkyl of from one through twelve carbon atoms,hydroxyalkyl of from one through twelve carbon atoms, cycloalkyl of fromthree through eight carbon atoms, aryl of from six through fourteencarbon atoms, alkaryl wherein the aryl moiety is from six throughfourteen carbon atoms and the alkyl group(s) substituted thereincontain(s) from one through twelve carbon atoms, aralkyl wherein thealkyl moiety is from one through twelve carbon atoms and the arylgroup(s) substituted therein contain(s) from six through fourteen carbonatoms, with formaldehyde and a compound of the formula III wherein R andR are alkyl of from one through twelve carbon atoms, and R R and N whentaken together form a secondary cyclic alkylene amino group containingfrom five through seven carbon atoms, to yield a corresponding compoundhaving in rings A and B of the steroid nucleus the structure we R,

R 11 wherein R and R each, and both taken together with N, have the samemeaning as above;

(2) mixing a thus produced corresponding compound resulting from step(1) with a compound selected from the group consisting of adialkylsulfate and an alkyl halide to yield a corresponding compoundhaving in rings A and B of the steroid nucleus the structure Eer ewherein R R and R are alkyl of from one through twelve carbon atoms andX is selected from the group consisting of alkylosulfate and halogen;

(3) mixing a thus produced corresponding compound resulting from step(2) with a base to yield a corresponding compound of Formula III, above.

6. A process in accordance with claim 5 wherein the compound of FormulaIII is 6-methylene-17a-hydroxy-4- pregnene-3,20-dione, the compound ofFormula I is hydroxy-3-methoxy-3,5-pregnadien-20-one, the compound ofFormula II is Gfl-piperidinomethyl-17a-hydroxy-4-pregnene-3,20-dione,the compound of Formula IV is the methiodide of the compound of FormulaII and the alkyl halide of step (2) is methyl iodide.

7. A process for the production of a steroid compound having in rings Aand B of the steroid nucleus the structure which comprises the steps of(1) mixing a corresponding steroid compound having in rings A and B ofthe steroid nucleus the structure wherein R and R are alkyl of from onethrough twelve carbon atoms, and R R and N when taken together form asecondary cyclic alkylene amino group containing from five through sevenmembers, with a compound selected from the group consisting of a dialkylsulfate and an alkyl halide to yield a corresponding compound having inrings A and B of the steroid nucleus the structure wherein R R and R arealkyl of from one through twelve carbon atoms and X is halogen;

(2) mixing a thus produced corresponding compound resulting from step(1) with a base to yield a corresponding compound of Formula III, above.

8. A process in accordance with claim 7 wherein the compound of FormulaIII is 6-methylene-17a-hydroxy-4- pregnene-3,20-dione, the compound ofFormula II is 65- piperidinomethyl-l7ot-hydroxy-4-pregnene-3,20-dione,the compound of Formula IV is the methiodide of the compound of FormulaII, and the alkyl halide of step (1) is methyl iodide.

9. A process for the production of a steroid compound having in rings Aand B of the steroid nucleus the structure 2 III which comprises mixingwith a base a corresponding compound having in rings A and B of thesteroid nucleus the structure XE IV wherein R R and R are alkyl of fromone through twelve carbon atoms and X is selected from the groupconsisting of an alkylosulfate and a halogen.

10. A process in accordance with claim 9 wherein the compound of FormulaIII is 6-methylene-17a-hydroxy 4-pregnene-3,20-dione and the compound ofFormula IV is the methiodide of 6fi-piperidinomethyl-17a-hydroxy-4-pregnene-3,20-dione.

11. A process for the production of a steroid compound having in rings Aand B of the steroid nucleus the structure H2 III which comprises thesteps of (1) mixing a corresponding steroid compound having in rings Aand B of the steroid nucleus the structure wherein R is selected fromthe group consisting of alkyl or from one through twelve carbon atoms,hydroxyalkyl of from one through twelve carbon atoms, cycloalkyl of fromthree through eight carbon atoms, aryl of from six through fourteencarbon atoms, alkaryl wherein the aryl moiety is from six throughfourteen carbon atoms and the alkyl group(s) substituted thereincontain(s) from one through twelve carbon atoms, aralkyl wherein thealkyl moiety is from one through twelve carbon atoms and the aryl group(s) substituted therein contain(s) from six through fourteen carbonatoms, with formaldehyde and a compound of the formula n HN wherein Rand R are alkyl of from one through twelve carbon atoms, and R, R and Nwhen taken together form a secondary cyclic alkylene amino groupcontaining from five through seven carbon atoms, to yield acorresponding compound having in rings A and B of the steroid nucleusthe structure CH N wherein R and R each, and both taken together with N,have the same meaning as above;

(2) heating a thus produced corresponding compound resulting from step(1) with a compound selected from the group consisting of an alkylhalide and a dialkyl sulfate to yield a corresponding compound having inrings A and B of the steroid nucleus the structure wherein R is selectedfrom the group consisting of alkyl of from one through twelve carbonatoms, hydroxyalkyl of from one through twelve carbon atoms, cycloalkylof from three through eight carbon atoms, aryl of from six throughfourteen carbon atoms, alkaryl wherein the aryl moiety is from sixthrough fourteen carbon atoms and the alkyl group(s) substituted thereincontain(s) from one through twelve carbon atoms, aralkyl wherein thealkyl moiety is from one through twelve carbon atoms and the arylgroup(s) substituted therein contain(s) from six through fourteen carbonatoms, and R R R and X have the same meaning as above;

(4) mixing a thus produced corresponding compound resulting from step(3) with water to yield a corresponding compound of Formula III, above.

12. -A process in accordance with claim 11 wherein the compound ofFormula III is 6-methylene-17ot-hydroxy-4- pregnene-3,20-dione, thecompound of Formula I is 170:- hydroxy-3-methoxy-3,S-pregnadien-ZO-one,the compound of Formula II is65-piperidinomethyl-l7a-hydroxy-4-pregnene-3,20-dione, the compound ofFormula IV is the methosulfate of the compound of Formula II and thedialkyl sulfate of step (2) is dimethyl sulfate.

13. A process for the production of a steroid compound having in rings Aand B of the steroid nucleus the which comprises the steps of (l)heating a corresponding steroid compound having III in rings A and B ofthe steroid nucleus the structure R II wherein R and R are alkyl of fromone through twelve carbon atoms, and R R and N when taken together forma secondary cyclic alkylene amino group containing from five throughseven members, with a dialkyl sulfate to yield a corresponding compoundhaving in rings A and B of the steroid nucleus the structure cu R,

I ea cum n:

e\ X R8 IV wherein R is selected from the group consisting of alkyl offrom one through twelve carbon atoms, hydroxyalkyl of from one throughtwelve carbon atoms, cycloalkyl of from three through eight carbonatoms, aryl of from six through fourteen carbon atoms, alkaryl whereinthe aryl moiety is from six through fourteen carbon atoms and the alkylgroup(s) substituted therein contain(s) from one through twelve carbonatoms, aralkyl wherein the alkyl moiety is from one through twelvecarbon atoms and the aryl group(s) substituted therein contain(s) fromsix through fourteen carbon atoms, and R R R and X have the same meaningas above; (3) mixing a thus produced corresponding compound resultingfrom step (2) with water to yield a corresponding compound of FormulaIII, above.

14. A process in accordance with claim 13 wherein the compound ofFormula III is 6-methylene-17a-hydroxy-4- pregnene-3,20-dione, thecompound of Formula II isGopiperidinomethyl-l7u-hydroxy-4-pregnene-3,20-dione, the compound ofFormula IV is the methosulfate of the compound of Formula VI is themethosulfate of 6fl-piperidinomethyl 17cchydroxy-3-methoxy-3,5-pregnadien-20-one, and the dialkyl sulfate of step(1) is dimethyl sulfate.

15. A process for the production of a steroid compound having in rings Aand B of the steroid nucleus the Hg III which comprises the steps of (1)mixing a corresponding compound having in rings A and B of the steroidnucleus the structure wherein R is selected from the group consisting ofalkyl of from one through twelve carbon atoms,

2 hydroxyalkyl of from one through twelve carbon atoms, cycloalkyl offrom three through eight carbon wherein R and R are alkyl of from onethrough twelve carbon atoms, and R R and N when taken together form asecondary cyclic alkylene amino group containing from five through sevencarbon atoms, to yield a corresponding compound having in rings A and Bof the steroid nucleus the structure R II wherein R and R each, and bothtaken together with N, have the same meaning as above;

(2) mixing a thus produced corresponding compound resulting from step 1)with hydrogen peroxide to yield a corresponding compound having in ringsA and B of the seroid nucleus the structure R1 Re n wherein R and Reach, and both taken together with N, have the same meaning as above;

(3) heating a thus produced corresponding compound resulting from step(2) to yield a corresponding compound of Formula III, above.

16. A process in accordance with claim 15 wherein the compound ofFormula III is 6-methylene-l7a-hydroxy-4- pregnene-3,20-dione, thecompound of Formula I is hydroxy-3-methoxy-3,S-pregnadien-ZO-one, thecompound of Formula H is GB-piperidininomethyl-17a-hydroxy-4-pregnene-3,20-dione and the compound of Formula V is the N-oxide of thecompound of 'Formula H.

17. A process for the production of steroid compound having in rings Aand B of the steroid nucleus the structure H2 III which comprises thesteps of (1) mixing a corresponding steroid compound having in rings Aand B of the steroid nucleus the structure wherein R and R are alkyl offrom one through twelve carbon atoms, and R R and N when taken togetherform a secondary cyclic alkylene amino group containing from fivethrough seven carbon atoms, with hydrogen peroxide to yield acorresponding compound having in rings A and B of the steroid nucleusthe structure mii m 3 o R v wherein R R and R are alkyl of from onethrough twelve carbon atoms;

(2) heating a thus produced corresponding compound resulting from step(1) to yield a corresponding compound of Formula III, above.

18. A process in accordance with claim 17 wherein the compound ofFormula III is G-methylene-17a-hydroxy-4- pregnene-3,20-dione, thecompound of Formula II is 6B-piperidinomethyl-17u-hydroxy-4-pregnene-3,20-dione and the compound ofFormula V is the N-oxide of the compound of Formula II.

19. A process for the production of a steroid compound having in rings Aand B of the steroid nucleus the structure which comprises heating acorresponding steroid compound having in rings A and B of the steroidnucleus the structure UNITED STATES PATENTS 3,159,643 12/1964 Kirk et a1260397.3

HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

260239.55 R, 239.55 A, 239.55 D, 239.57, 397.2, 397.3, 3974, 397.45,397.47

